Focused Heme Pharmacology

Front 1

6-Mercaptopurine
(Class, MOA, uses, tox, resistance)

Back 1

1. Antimetabolite (pruine analog)
2. feedback inhibition of purine synthesis and some minor incorporation into DNA
3. ALL, AML, CML
4. Myelosupression, hepatotoxicity, teratogenic, nausea/vomiting
5. Decreased activity of activating enzyme (HGPRT)

Front 2

Alkylating Agents
(Classes)

Back 2

1. Platinum compounds (specifically target DNA)
2. Azidines
3. Alkyl Sulfonates
4. Methylating agents
5. Nitrogen mustards (cyclophosphamide, mechlorethamine)
6. Nitrosoureas
7. Other

Front 3

Alkylating Agents
(MOAs)

Back 3

1. transfer alkyl groups to macromolecules - Mostly DNA N-7 and O-6 positions on Guanine

**this causes 3 effects***
1. inactivation of genes by base mispairing
2. DNA strand X-linking
3. DNA strand breakage

**AAs damage all macromolecules (not just DNA) but normal cells just replace themselves**

Front 4

Alkylating Agents
(Uses, tox, resistance, combo drugs)

Back 4

1. (Very broad use) many cancers
2. Reproductive tox, alopecia, GI, 2ary cancers, nausea/vomiting
3. increased DNA repair, decreased permeation, increased scavengers like GSH, UPREGULATION OF MDR PROTEIN - EFFLUX -
4. AAs - generally not crossreactive with other AAs, so they're used in combo with eachother

Front 5

Anthracyclines
(Class, name 3 drugs)

Back 5

1. Antitumor antibiotics
2. Daunorubicin (ALL, AML), Doxorubicin (Adriamycin or Hydroxydaunarubicin) (Very Broad)
3. Idarubicin (AML)

Front 6

Anthracyclines
(MOA(3), resistance, tox)

Back 6

1. DNA intercalation - blocking topo II, Generates 02 rads, disrupts cell signaling by binding to membrane - hydrophobic
2. Upregulation of MDR
3. Cardiotoxicity

Front 7

Antimetabolites
(Major classes and their corresponding agents)

Back 7

1. Purine analog (6-Mercaptopurine)
2. Folate analog (MTX)
3. Pyrimidine analog (5-Fluorouracil)
4. Ribonucleotide Reductase Inhibitor (Hydroxyurea)

Front 8

6-Mercaptopurine
(MOA)

Back 8

1. Purine analog that inhibits RNA and DNA synthesis (ATP and GTP are required for metabolism)

Front 9

Methotrexate
(discuss MOA)

Back 9

1. THF is needed to carry methyl groups to build purines/pyrimidines. It requires a specific transporter for uptake that is different in normal cells. We use that difference to selectively kill neoplastic cells. Synthetic Leucovorin "rescues" normal cells that are deficient in THF b/c they can pick it up when neoplastic cells cannot.

Front 10

5-Fluorouracil
(MOA)

Back 10

1. Pyrimidine analog, binds Thymidylate synthase (TS). Without this enzyme, no dTMP will be made.

Front 11

Hydroxyurea
(MOA)

Back 11

1. binds and inhibits ribonucleotide reductase, preventing synthesis of dNDPs from NTPs

Front 12

Epipodophyllotoxins
(Name 2 drugs, class, MOA, uses, tox, resistance)

Back 12

1. Etoposide, Teniposide
2. Natural - topoisomerase inhibitor
3. binds topo II, double strand breaks
4. Testicular tumors, small cell carcinomas (lung)
5. Leukopenia, nausea/vomiting
6. MDR and topo II mutants

Front 13

Fludarabine
(Class, MOA, Uses, Tox)

Back 13

1. Antimetabolite - new generation purine analog)
2. incorporated into DNA and RNA and acts as a chain terminator, inhibits DNA pol, DNA ligase, RNReductase, induces apoptosis
3. CLL, low-grade lymphomas
4. Bone marrow suppression, CNS tox

Front 14

Cladribine
(Class, MOA, Uses, Tox)

Back 14

1. Antimetabolite - new generation purine analog
2. Causes doublestrand breaks, depletes NAD+ and ATP
3. Hairy Cell Leukemia, CLL, low-grade lymphomas
4. Bone marrow suppression

Front 15

Glucocorticoids
(Name 3 drugs, Uses, Resistance, Tox, MOA)

Back 15

1. Prednisone, Dexamethasone, Methylprednisolone
2. Leukemias and Lymphomas (high doses), Prednisone is used in combo therapy **its activated in the liver**
3. decreased glucocorticoid receptor expression/mutation
4. Cushing's Syndrome, infection, Na retention, OSTEOPOROSIS, hypokalemia, muscle wasting
5. Glucocorticoid receptors are expressed on every cell but RBC's/platelets, toxic to T-cells, bind cytoplasmic receptors are then brought to nucleus to regulate transcription (regulating proliferation and differentiation signaling)

Front 16

Imatinib (Gleevec)
(Class, MOA, Uses, Alternate treatments)

Back 16

1. Protein Kinase Inhibitors
2. target BCR-ABL tyrosine kinase protein which doesn't exist in normal cells
3. CML, ALL
4. Dasatinib (same MOA, but more "promiscuous" - has more activity to more growth factor receptors. Nilotinib (has activity at the PFGF receptor and c-Kit)

Front 17

Interferon Alpha
(Class, Uses, Tox, MOA)

Back 17

1. Cytokine - Immunostimulatory agent
2. Hairy Cell Leukemia, Renal Cell Carcinoma, Kaposi's Sarcoma
3. mild, flu-like symptoms, cardiomyopathy (rare), hypotension
4. Interfere with viral RNA protien synthesis, binds to stimulatory immune receptors that activates phagocytes/T-cells/NK cells/macrophages, helps the body mount an immune response

Front 18

Bortezomib (Velcade)
(class, MOA, clinical use)

Back 18

1. Proteosome inhibitor
2. Reversibly inhibits proteasome activity - transient inhibition causes normal cells to arrest and recover, but cancer cells build up damaged proteins and structure, causing the cell to apoptose
3. relapsed or refractory multiple myeloma

Front 19

Vinca Alkaloids
(class, MOA, specific drugs (2), resistance, clinical use for each drug, toxicity)

Back 19

1. microtubule inhibitors (natural product)
2. bind to tubulin dimers forming a complex that cannot assemble into a microtubule...mitotic spindle disappears and cells arrest in metaphase
3. Vincristine (Oncovin) and Vinblastine (Velban)
4. MDR gene over-expression, tubulin mutants
5. VC: Hodgkin's and Non-Hodgkin's
VB: Hodgkin's
6. Peripheral Neuropathy! VB is strongly myelosuppressing, not used as commonly as VC

Front 20

Rituximab (Rituxan)
(class, MOA, clinical use, "smart bomb")

Back 20

1. protein kinase inhibitor (monoclonal Ab)
2. humanized Ab binds to CD20 (on most B-cell non-Hodgkin's lymphomas/leukemias). Binding CD20 inhibits cell activation, cell cycle progression, and promotes Ab-mediated cytotoxicity toward overexpressing tumor cells.
3. most B-cell non-Hodgkin's lymphoma, leukemias
4. can radiolabel this drug with gamma-ray emitting isotopes 131-I and 90-Y to create a radioactive "smart bomb" to the cells you want to get rid of.

Front 21

Procarbazine/Dacarbazine
(class, MOA, resistance, clinical use, toxicity)

Back 21

1. alkylating agent
2. "miscellaneous" DNA modifying agent, requires metabolic activation but mechanism is poorly understood...produces oxygen free radicals and chromosomal breaks
3. resistance occurs quickly, unknown mechanism
4. Procarbazine: Hodgkin's (MOPP, BEACOPP)
Dacarbazine: Hodgkin's and Non-Hodgkin's (ABVD)
5. leukopenia, thrombocytopenia, nausea/vomiting
ABVD), Non-Hodgkin's (ABVD)
3.

Front 22

Methotrexate
(class, MOA, resistance, clinical use, toxicity)

what is this drug used in combination with?

Back 22

1. antimetabolite (folate analog)
2. inhibits dihydrofolate reductase (DHFR), which blocks the formation of DNA precursors
3. gene amplification of DHFR, mutant DHFR
4. ALL, Burkitt's Lymphoma
5. hepatotoxicity (reversible), intestinal epithelium (mucositis), damage to BM

USED IN COMBO WITH: Leucovorin (is a synthetic folic acid to rescue normal cells that have a cellular transporter to uptake folate - cancer cells don't have this)

Front 23

L-Asparaginase
(MOA, Resistance, Class, Uses, Tox)

Back 23

1. Exploit the difference in Asparagine levels in tumor vs. normal cells. Depletion of plasma Asp effects tumor cells selectively. "Rescue" normal cells with Leucovorin.
2. Increased serum proteases, specific antibiotics
3. Anti-tumor antibiotic
4. ALL
5. allergic reaction (no effect on bone marrow, GI, Hair)